Obesity is a public health epidemic, with no effective, feasible treatments. The recent increase in obesity, particularly in children, will bring an increase in related diseases such as diabetes and heart disease. Although the recent increase in obesity is due to changes in environmental factors such as diet and exercise, an individual's susceptibility to these environmental triggers varies with their genetic background. Knowledge of the causal genetic factors would indicate which pathways are altered in patients and would therefore guide the development effective preventive measures and treatments. No genetic variants have been proven to contribute to obesity in the general population, but recent research has provided tantalizing clues. Seventy-one common genetic variants called SNPs (single nucleotide polymorphisms) in 55 genes have been reported to be associated with obesity, but none have been replicated consistently. A recent meta-analysis of association studies suggests that many of these associations will turn out to be spurious, but also that some of these variants will represent true causal risk factors for obesity, and that large cohorts are required to make this distinction. The goal of this proposed research is to determine which of these previously reported associations represent real obesity risk factors and which are false leads. To accomplish this goal, we plan to test the 25 genes for association to obesity in multiple large, well-powered populations of lean and obese individuals (n > 4,000). To more completely characterize these candidate genes and to search for causal variants that might have led to the originally reported association, we will test not only the previously studied variants but also survey common variation throughout these genes by exploiting patterns of genetic variation called haplotypes. This approach will allow us to test the entire gene for causal variant(s) that might explain the original reported association with obesity. For any variants that we can validate as associated with obesity, we will also examine their role in obersity-related diseases (diabetes and cardiovascular disease), and explore gene-environment interactions with diet and physical activity. Finally, to set the stage for future research in early-onset obesity, we will collect a pilot cohort of children for genetic epidemiologic studies of obesity.